Much of our understanding of the neurobiological basis of cocaine abuse in humans has been based on investigations carried out in rodents. It has been only recently that studies imaging living human brain with positron emission tomography have begun to address these questions directly. Results from these studies suggest that the cortex may play an important role in mediating the response to cocaine in humans and that persistent changes in dopaminergic systems and cerebral metabolism accompany chronic cocaine abuse. Unfortunately, the nature of human research precludes a systematic evaluation of many of the variables that might affect these neurobiological markers. The lack of control over environmental factors, incomplete and varied drug histories, the high incidence of polydrug abuse, and the presence of comorbid psychopathology can confound the interpretation of data from human studies. Many of these problems, however, can be obviated by the use of a non-human primate model of cocaine self-administration. This model is particularly appropriate because the connectional and chemical anatomy of the dopaminergic mesolimbic system, considered a critical substrate of the reinforcing effects of abused drugs as well as natural reinforcers, is far more complex in the monkey than in rodent and, as such, more closely homologous to that of the human. We propose the use of cocaine self-administration by cynomolgus monkeys to 1) identify the neurobiological changes associated with early and long-term exposure to and abstinence from self-administered cocaine, 2) determine behavioral sequelae of abstinence from cocaine, and 3) relate the neurobiological changes directly to self-administration behavior in the same animal. To accomplish these goals we will: 1) identify the neuroanatomical substrates involved in the early response of cocaine self-administration using the quantitative autoradiographic 2- (14C]deoxyglucose method to measure changes in metabolic activity during the initial exposure of monkeys to cocaine, 2) measure changes in brain metabolism, dopamine transporters and D2 and D3 receptors resulting from long-term cocaine self-administration. Quantitative in vitro receptor autoradiography and in situ hybridization will be used to assess alterations in pre- and postsynaptic elements of the dopaminergic system. 3) identify the changes in brain metabolism, D2 and D3 receptors, and dopamine transporters resulting from cocaine abstinence. Finally, we have designed these experiments to determine behavioral correlates of "craving" which accompanies short-term abstinence from cocaine. The results of the proposed studies will provide a clearer picture of the neurobiological and behavioral basis of cocaine abuse in humans.